Abstract
Human brain lesions in the perinatal period result in life-long neuro-disabilities impairing sensory-motor, cognitive, and behavior functions for years. Topographical aspects of brain lesions depend on gestational age at the time of insult in preterm or term infants and impaired subsequent steps of brain development and maturation. In mice, the Rice-Vannucci procedure of neonate hypoxia-ischemia (HI) was used at 5 days (P5) or P10, mimicking the development of 30 week-gestation fetus/preterm newborn, or full-term infant, respectively. Transcription response to HI was assessed at 3, 6, 12, and 24 h after insult, using micro-array technology. Statistical Pathway and Gene Ontology terms enrichments were investigated using DAVID®, Revigo® and Ingenuity Pathway Analysis (IPA®) to identify a core of transcription response to HI, age-specific regulations, and interactions with spontaneous development. Investigations were based on direction, amplitude, and duration of responses, basal expression, and annotation. Five major points deserve attention; (i) inductions exceeded repressions (60/40%) at both ages, (ii) only 20.3% (393/1938 records) were common to P5 and P10 mice, (iii) at P5, HI effects occurred early and decreased 24 h after insult whereas they were delayed at P10 and increased 24 h after insult, (iv) common responses at P5 and P10 involved inflammation, immunity, apoptosis, and angiogenesis. (v) age-specific effects occurred with higher statistical significance at P5 than at P10. Transient repression of 12 genes encoding cholesterol biosynthesis enzymes was transiently observed 12 h after HI at P5. Synaptogenesis appeared inhibited at P5 while induced at P10, showing reciprocal effects on glutamate receptors. Specific involvement of Il-1 (interleukin-1) implicated in the firing of inflammation was observed at P10. This study pointed out age-differences in HI responses kinetics, e.g., a long-lasting inflammatory response at P10 compared to P5. Whether the specific strong depression of cholesterol biosynthesis genes that could account for white matter-specific vulnerability at P5 or prevent delayed inflammation needs further investigation. Determination of putative involvement of Il-1 and the identification of upstream regulators involved in the delayed inflammation firing at P10 appears promising routes of research in the understandings of age-dependent vulnerabilities in the neonatal brain.
Highlights
Cerebral palsy is the most severe motor developmental disability in children, accompanied by sensorial deficits, cognitive, language, and behavioral impairments diversely associated
White matter in preterms born at 28–34 PC weeks has a special vulnerability, clearly associated with oligodendroglia and connectome differentiation stage at this time, whereas gray matter appeared more sensitive in the late gestation and later in the postnatal period when N-methyl-D-aspartate (NMDA)-type glutamate receptors are functional in neurons
386 genes (20% of the total) showed HI-induced regulations in both postnatal day 5 (P5) and P10 brains, and indicating that the majority of transcription effects were specific of one age (Figure 2A)
Summary
Cerebral palsy is the most severe motor developmental disability in children, accompanied by sensorial deficits, cognitive, language, and behavioral impairments diversely associated. The relationship between brain lesions and delayed children’s disabilities is less stringent, indicating that common causes have distinct brain consequences depending on brain maturity. White matter in preterms born at 28–34 PC weeks has a special vulnerability, clearly associated with oligodendroglia and connectome differentiation stage at this time, whereas gray matter appeared more sensitive in the late gestation and later in the postnatal period when N-methyl-D-aspartate (NMDA)-type glutamate receptors are functional in neurons. The common triggers recorded are ischemia when blood flow is decreased, oxidative stress and inflammation (Hagberg et al, 2015). Perfusion arrest and reperfusion are common in preterm having fluctuant hemodynamics and immature regulation of cerebral blow flow (Tuor and Grewal, 1994). Reperfusion leads to oxidative stress and inflammation
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